(±)-1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolenecarboxylic acid, commonly known as gatifloxacin, is a synthetic broad-spectrum antibacterial agent for oral or intravenous administration.
U.S. Pat. No. 4,980,470 (cf European Patent 230,295), discloses the synthesis of gatifloxacin via the substitution of 2-methyl piperazine on the 9,10-difluoro carboxylic derivative. The reaction is described to occur in the absence of solvent or in the presence of organic polar solvent such as DMSO, pyridine, dimethylformamide, alcohol, water or hexamethylphosphoric amide (See '470 patent paragraph 3, line 52). This reaction can reportedly be carried-out in the presence of an acid acceptor such as triethylamine, diazabicyclo bases, or potassium carbonate. According to example 3 of the '407 patent, the yield of this reaction in DMSO is 20%.
The reaction conditions under which gatifloxacin is synthesized are reported to effect the yield and purity of the products obtained. Some common impurities in gatifloxacin include the following:
Desmethyl gatifloxacin (DesMe-GTF), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(piperazinyl)-4-oxo-3-quinolinecarboxylic acid, is an impurity in gatifloaxacin:
hydroxy gatifloxacin (OH-GTF), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-hydroxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid:
dimethyl gatifloxacin (DiMe-GTF), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-hydroxy-7-(3,4-dimethyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid:
anti-gatifloxacin (Anti-GTF), 1-cyclopropyl-7-fluoro-1,4-dihydro-8-hydroxy-6-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid:
2-methyl piperazine gatifloxacin (2-Me-GTF), 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(2-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid:

In Korean Journal of Medicinal Chemistry 1996, Vol.6, No 2,157-161 the nucleophilic substitution on GTF-acid is described in the presence of basic aluminium oxide or basic ion-exchange resins. The authors reported that they produced gatifloxacin with a yield above 85%. The present inventors reproduced several times these experiments in the same experimental conditions or modified conditions using the same catalysts and were only able to achieve yields of about 50%.
In U.S. Pat. No. 4,997,943 to Sankyo, the authors described the synthesis of gatifloxacin hydrochloride (See example 22 thereof) via a borate intermediate that activates the position 7 of the ring that will be substituted by the 2-methylpiperazine. This boron chelate allowed the authors to run the reaction at ambient temperature and to get a yield of 38%.
In U.S. Pat. No. 5,157,117, Kyorin described the synthesis of another borate intermediate suitable for industrial process. This chelate should allow the authors to produce gatifloxacin in milder experimental conditions and reportedly in an overall yield of 76%.
The synthesis of levofloxacin is the same type of synthesis, i.e. a nucleophilic substitution of N-methylpiperazine (instead of 2-methylpiperazine) in position 7 of a quinolone.
In U.S. Pat. No. 5,053,407, directed to levofloxacin, the same reaction conditions as for gatifloxacin has been also described to provide 51% yield (example 6). In example 16 of the '407 patent, the same substitution is done through of a boron chelate to obtain 65% of levofloxacin.
U.S. Pat. Nos. 5,051,505 and 5,539,110 described the synthesis of levofloxacin in presence of phase transfer catalyst in order to allow less drastic reaction conditions. U.S. Pat. No. 5,155,223 describes the synthesis of levofloxacin in presence of water.
There is a need for a single-step synthetic route to gatifloxacin that allows manufacture of the product in good yield under mild conditions and in high purity.